Abstract
The pregnane X receptor (PXR) is a nuclear receptor (NR), involved in the detoxification of xenobiotic compounds. Recently, its presence was reported in the human vasculature and its ligands were proposed to exhibit anti-atherosclerotic effects. Since platelets contribute towards the development of atherosclerosis and possess numerous NRs, we investigated the expression of PXR in platelets along with the ability of its ligands to modulate platelet activation. The expression of PXR in human platelets was confirmed using immunoprecipitation analysis. Treatment with PXR ligands was found to inhibit platelet functions stimulated by a range of agonists, with platelet aggregation, granule secretion, adhesion and spreading on fibrinogen all attenuated along with a reduction in thrombus formation (both in vitro and in vivo). The effects of PXR ligands were observed in a species-specific manner, and the human-specific ligand, SR12813, was observed to attenuate thrombus formation in vivo in humanised PXR transgenic mice. PXR ligand-mediated inhibition of platelet function was found to be associated with the inhibition of Src-family kinases (SFKs). This study identifies acute, non-genomic regulatory effects of PXR ligands on platelet function and thrombus formation. In combination with the emerging anti-atherosclerotic properties of PXR ligands, these anti-thrombotic effects may provide additional cardio-protective benefits.
Highlights
IntroductionNuclear receptors (NRs) are well characterised for their genomic functions (transcriptional regulation), less is known about their non-genomic roles
Nuclear receptors (NRs) are well characterised for their genomic functions, less is known about their non-genomic roles
The protein was immunoprecipitated from platelet lysates using a mouse anti-pregnane X receptor (PXR) antibody and its presence was confirmed by immunoblotting with a rabbit anti-PXR antibody (Fig. 1A)
Summary
Nuclear receptors (NRs) are well characterised for their genomic functions (transcriptional regulation), less is known about their non-genomic roles. Several NRs (such as LXR, PPARα/β/γ, RXR, RAR and FXR) have been identified in platelets, which upon ligation regulate platelet activity, thrombosis and haemostasis through a variety of mechanisms in a non-genomic manner[1,2,3,4,5,6,7]. Inter-species differences in the ligands that activate PXR have been reported. PXR was reported to be expressed in the human vasculature (blood vessels, aortic endothelial and smooth muscle cells), where it functions to detoxify circulating toxins and avert vascular damage by upregulating CYP 3A, 2B and 2C activity[18]. Treatment of platelets with PXR ligands (SR12813 or rifampicin) attenuated platelet functions and thrombus formation (in vitro and in vivo) through a mechanism that is associated with the down-regulation of Src-family kinase (SFK) signalling
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